Parkinson's disease (PD) affects about 1 million people in North America. Medications, such as levodopa, and some surgical approaches are available for PD, but offer only symptomatic therapy. New information contribute to current optimism that gene therapy might correct the molecular disturbances of PD, alleviate the symptoms of the illness and/or in retarding disease progression. Setbacks in gene therapy for other diseases underscore the importance of a purposely deliberate and careful approach that demands substantial assurances of safety and potential efficacy in advance of human testing. It is this philosophy of conservatism that will characterize the activities of our group. A coordinated stepwise progression from basic research through exhaustive preclinical evaluation prior to clinical testing is required. A multicenter, multidisciplinary collaborative group (The PD Gene Therapy Study Group [PDGTSG]) has formed and seeks support for those activities that will lead to a large-scale clinical trial of gene therapy for patients with PD. The PDGTSG consists of three different components: Cores, Principal Projects, and Pipeline Projects. Core A. Administrative Core (PI: Dr. Federoff): Houses a Steering Committee, and Vector (Chair: Dr. Lowenstein), Human Subjects/Clinical Assessment (Chair: Dr. Kurlan), Bioethics (Chair: Ms. Greenlaw), Intellectual Property (Chair: Ms. Hunter) and Biostatistics Modules (Chair: Dr. Oakes). Provides for the coordination of budgeting, committee scheduling, reports, progress preparation, and interface with NINDS staff, the clinical, scientific and lay community. Core B. Biological Measurement Core (PI: Dr. Federoff: Functions in the application shared quantitative measurements. Houses the database and the bank of vector constructs used in all studies. Project I. "Enzymatic Gene Transfer in MPTP Monkeys" (PIs: Bankiewicz and Kordower) Will comprehensively evaluate two vector platforms (rHIV and rAAV), each transducing the identical AADC gene cassette in the standardized non-human primate model. Project II. "Trophic Gene Transfer in MPTP Monkeys" (PIs: Bankiewicz and Kordower) Will comprehensively evaluate two vector platforms (rHIV and rAAV), each transducing the identical regulated GDNF gene cassette in the standardized non-human primate model. PIPELINE PROJECTS 0PPs) Focus 1: 1reproved regulation of gene expression PP I. "Tet-Regulated Vectors for Parkinson's Disease" (PI: Bohn). PP II. "Engineering RNA Switches that Respond to Dopamine and its Analogs" (PI: Breaker). Focus 2: Development of new vector platforms for application in PD disease models. PP III. "High Capacity Gutless Adenovirus" (PI: Lowenstein). PP IV. "Development of Integrating HSV Amplicons for Parkinson's Disease" (PI: Bowers). Focus 3: Development of methods to effectively control and distribute lentiviral and AAV vectors throughout the non-human primate brain. PP V. "Enhanced Delivery Methods for Widespread Distribution of Lentiviral and AAV Vectors" (PI: Bankiewicz). PP VI. "Analysis of Vector and Transgene Product Transport and Distribution" (PI: Bankiewicz) Focus 4: Development of imaging methods to detectgene expression. PP VII. "Design, Construction and Evaluation of PET Imaging Gene Surrogate" (PI: Muhkerjee). Focus 5: Development of a hioethics approach to PD gene therapy. PP VIII. "Measuring and Explaining PD Patients' Participation Preferences Regarding Phase I Studies in Gene Transfer Therapy" (PI: Kim).